The Child Who Needs a Liver Transplant

Abstract

Liver transplantation (LT) is standard care for children with end-stage, irreversible liver disease. Multidisciplinary medical management and improvements in surgical techniques have led to improved survival. The common indications for pediatric liver transplantation are cholestatic diseases, especially biliary atresia (43%), metabolic diseases (13%), acute liver failure (11%) and hepatic tumours (Table 11.1).

Liver transplantation (LT) is standard care for children with end-stage, irreversible liver disease. Multidisciplinary medical management and improvements in surgical techniques have led to improved survival. The common indications for pediatric liver transplantation are cholestatic diseases, especially biliary atresia (43%), metabolic diseases (13%), acute liver failure (11%) and hepatic tumours (Table 11.1).

Table 11.1 Indications for liver transplantation

11.1 Children with Chronic Liver Failure

Many children with chronic liver disease develop cirrhosis and portal hypertension despite well-compensated liver function. However, gradual deterioration in hepatic function, failure of nutrition, growth and difficulty in maintaining normal life are acceptable parameters to consider liver transplantation. Clinical features include malnutrition, jaundice, ascites and hepatosplenomegaly (Fig. 11.1) (see also Chapters 1 and 7). The timing of transplantation may be difficult, but is based on: a persistent rise in total bilirubin >150 mmol/l, prolongation of prothrombin ratio (INR >1.4) and a fall in serum albumin <35 g/l. These parameters are included in the international Pediatric End-Stage Liver Disease Score (PELD) used to prioritise the waiting list.

Fig. 11.1

This child with biliary atresia shows deep jaundice and malnutrition as evidenced by the muscle wasting and lack of fat stores. She received a successful transplant

11.2 Children with Acute Liver Failure

The most common causes of acute liver failure in neonates are; Herpes Simplex, HHV6; and inborn errors of metabolism or neonatal hemochromatosis (GALD) (see Chapter 2), (Fig. 11.2). In older children: Auto-immune hepatitis , drug induced liver disease , Paracetamol overdose or metabolic diseases such as Wilson’s disease (see Chapters 6 and 7). The indications for transplantation in acute liver failure are agreed internationally. The UK Liver Advisory Group recommends that children who have a persistent coagulopathy (prothrombin time > 40; INR >4), encephalopathy without evidence of irreversible brain damage are candidates for transplantation, provided there is no irreversible multi system involvement.

Fig. 11.2

This infant had acute liver failure from an echo virus infection. Note the small liver and his obvious distress

11.2.1 Un-resectable Liver Tumours

Liver tumours which cannot be completely resected are considered for transplantation, (see Chapter 4) as long as there are no extra-hepatic metastases (Fig. 11.3).

Fig. 11.3

Axial intravenous contrast enhanced fat suppressed T1 weighted image of the liver and coronal STIR sequence of the liver reveal multifocal lesions of tumour involving more than 3 sectors of liver. This mean the tumour is unresectable and therefore an indication for transplantation

11.2.1.1 Transplantation Process

The operative procedure of liver transplantation is well standardised. The essential components include a thorough evaluation of the child and family to identify severity of disease, absence of contraindications, provide education and counselling prior to listing for transplant, surgical procedure and post procedure complications. The paucity of size matched donors mean that most children receive cut-down or split liver grafts from adult livers or relatives (Fig. 11.4a–c).

Fig. 11.4

In preparing a liver for splitting, the liver parenchymal is divided by harmonic device after carefully dividing the hepatic artery, portal vein, bile duct and hepatic vein (a). (b) At completion two liver grafts are produced with full set of hepatic vein, hepatic artery, portal vein and bile duct. (c) A back table cholangiogram is useful for guidance when dividing the parenchyma, segment 2 and 3 duct joining to form a single left hepatic duct (LHD), Red dotted line indicates the liver parenchymal dividing plane

11.2.1.1.1 Post-transplant Management

The first 24–48 h following transplant are focused on establishing good respiratory and hemodynamic support , maintaining fluid balance, renal output and ensuring good pain relief. Graft function is assessed with regular liver function and coagulation tests. Liver ultrasound with colour flow Doppler is performed for the first 5–7 days and later as clinically indicated to confirm vascular patency and the absence of biliary dilatation (Fig. 11.5).

Fig. 11.5

Ultrasound Doppler of the transplant liver reveals normal Doppler traces of (a) hepatic artery, (b) portal vein and (c) hepatic vein with normal liver echogenicity

Most complications in the early post-transplant period (first 2 weeks) are related to technical factors such as hepatic artery thrombosis (HAT) . (Fig. 11.6) or portal vein thrombosis or stenosis (PVT) Portal vein stenosis is managed by angiography and balloon dilatation (Fig. 11.7d–f). Hepatic outflow obstruction (HVO) is managed with angiography and balloon dilatation (Fig. 11.8a–c). Inferior vena cava thrombosis/stenosis may require venography and dilation (Fig. 11.9).

Fig. 11.6

(a–c) Intravenous contrast enhanced CT scan of the abdomen reveals narrowing of the hepatic artery at its origin from coeliac axis with complete occlusion distally. (d)This gross image from an allograft liver removed at the time of retransplantation shows hepatic artery thrombosis marked with an arrow. (e) transverse section through the hepatic artery showing occlusion of the lumen by thrombus

Fig. 11.7

(a) Ultrasound scan showing narrowing with pre-stenotic dilatation (b) Ultrasound scan with pre and post stenotic dilatation (marked with star) amd echogenic material in the post-stenotic dilatation (? Thrombus) marked with arrow. (c) Intravenous contrast axial CT scan of the abdomen reveals caliber change at the site of anastomosis (arrow) of the portal vein in keeping with portal vein stenosis. (d) Angiography showing narrowing at the anastomosis (e) dilatation balloon waist confirming narrowing (f) post dilatation, no narrowing, post stenotic dilatation still present

Fig. 11.8

(a) Venogram of hepatic vein reveals stenosis of the hepatic venous junction with IVC (b) balloon dilatation (c) post dilatation

Fig. 11.9

IVC narrowing. CT scan abdomen showing compression of IVC (arrows) coronal and lateral view

11.2.2 Biliary Complications

Bile leak, anastomotic strictures, and non-anastomostic strictures of the donor bile duct have a reported incidence of 10–20% depending on the graft type. Ultrasound and MRI are the principal imaging modalities used for detection of these complications (Fig. 11.10).

Fig. 11.10

(a) Axial T2 sequence of liver reveals severe narrowing of all the biliary ducts of the transplant liver at their junction with the Roux-en-y in keeping with multiple biliary strictures (b) Coronal T2 sequence showing stricture at duct to duct anastomosis in a full size graft (c) Percutaneous Transhepatic Cholangiogram of biliary system reveals severe narrowing at the junction of hepatic bile ducts with the roux-en-y with proximal dilatation in keeping with multiple biliary strictures

Early biliary complications are best treated by immediate surgery and re-anastomosis if required. Late stricture formation may be satisfactorily dealt with by endoscopic or percutaneous balloon dilatation or stenting. Histology will demonstrate large bile duct obstruction (Fig. 11.11).

Fig. 11.11

This portal tract demonstrates biliary features (H&E ×100). The bile duct itself ‘BD’ is normal, it is close to, and a similar size to, the hepatic artery ‘A’. There is a normal portal vein ‘PV’. The stars mark biliary ductules at the margins of the portal tract, copper associated protein is often visible on an orcein stain corroborating biliary changes. In the allograft this should prompt consideration of large bile duct obstruction, hepatic artery thrombosis can also cause this picture referred to as ischaemic cholangiopathy

Diaphragmatic paresis and herniae: are rare complications of liver transplantation. Cross clamping of the IVC at the level of the diaphragmatic hiatus, trauma at operation (dissection and diathermy) are some of the contributory factors (Fig. 11.12).

Fig. 11.12

T2 coronal sequence of the abdomen reveals abnormally raised right dome of diaphragm and transplant liver in keeping with right diaphragmatic paralysis

11.3 Medical Complications

Common medical complications post-transplant include acute or chronic rejection, bacterial, viral, fungal and opportunistic infections, renal dysfunction, hypertension. Of particular concern is post-transplant lympho-proliferative syndrome (PTLD) associated with a primary Epstein Barr Virus (EBV).

Rejection: Acute rejection is suspected if a child presents with fever, malaise, a tender graft and loose stools. Biocmical liver function tests demonstrate abnormal hepatic transaminases, gamma glutamyl transpedtidase and raised alkaline phosphatase. Diagnosis is confirmed by histology. The grade of rejection is assessed according to established histological criteria on a scale of 0–4 (Fig. 11.13).

Fig. 11.13

Acute cellular rejection H&E ×400. The triad of features indicating acute, T cell mediated, rejection are; a portal inflammatory infiltrate often including eosinophils (marked by stars) damage to the bile duct ‘BD’ the arrow is pointing to infiltration of biliary epithelium by inflammatory cells and endothelitis. This latter lesion is seen in the portal vein ‘PV’ note that instead of a smooth endothelial lining inflammatory cells infiltrate beneath the endothelium and cells appear to ‘drop-off’ into the lumen. ‘A’ denotes the hepatic artery

Acute rejection is treated with three doses of intravenous methyl prednisolone (10 mg/kg) on 3 successive days with adjusted baseline immunosuppression. If corticosteroid resistant acute rejection develops, other therapies include addition of mycophenolate mofetil, sirolimus, antithymocyte globulins (ATG) or monoclonal anti-CD3 antibodies.

Chronic rejection : occurs at any time. It may respond to immunosuppression, but is usually irreversible which is manifested by disruption of bile duct radicals with development of the vanishing bile duct syndrome (Fig. 11.14). Re-transplantation may be required.

Fig. 11.14

(a) Foam cell arteriopathy in chronic rejection. This is an image (H&E ×200) of a large hepatic artery branch at the hilum of an allograft liver removed at the time of retransplantation. The arrow is pointing to the internal elastic lamina. The lumen of the vessel is entirely replaced by foamy macrophages. (b). Chronic rejection, H&E ×400. In contrast to the acute situation, illustrated in Fig. 11.13, there are barely any inflammatory cells here. Two profiles of a bile duct are present in this portal tract, marked by arrows, the accompanying artery is labelled ‘A’. These ducts have a ‘dysplastic’ appearance, many nuclei have been lost and with progression the duct disappears entirely. The portal vein ‘PV’ has a normal appearance

Patients in the post-transplant period have reduced immunity and are prone to bacterial, viral, fungal and parasitic infections. Gram-positive bacteria predominate over gram-negative bacteria. The commonest viral infections are Cytomegalovirus (CMV) and Epstein Barr virus (EBV). Epstein-Barr virus (EBV) is the main cause of post-transplant lympho-proliferative disorder (PTLD) which usually occurs in EBV negative recipients who receive an EBV positive donor. Patients may present with non-specific symptoms, anaemia, diarhoea and/or lymphadenopathy. The diagnosis is made on detecting an elevated plasma EBV PCR, compatible radiology (Fig. 11.15) and confirmed by histology (Fig. 11.16).

Fig. 11.15

Intravenous contrast enhanced coronal CT scan of the abdomen reveals hypo dense lesions within the liver, spleen and mesentery in keeping with PTLD

Fig. 11.16

(a) These grossly identifiable nodules of PTLD were seen in an allograft liver removed at the time of retransplantation. (b) Post transplant lymphoproliferative disorder (PTLD) encompasses a spectrum. This lesion indicates the malignant end of the spectrum. The image shows a monotonous population of blast-like lymphoid cells (H&E ×400) as seen in lymphomas. The inset shows nuclear positivity for Epstein-Barr virus encoded early RNAs (EBERs). The patient had suffered from rejection and had therefore received augmented immunosuppression

Management strategies include reduction of immunosuppression, which may require complete withdrawal, Rituximab, an anti-CD 20 monoclonal antibody which reduces B cells and should be used with replacement immunoglobulin therapy. If no response, then standard anti-lymphoma chemotherapy is required. Mortality varies from 20 to 70%.

Occasionally, the graft develops nodular regenerative hyperplasia related to altered blood flow through the liver (Fig. 11.17).

Fig. 11.17

Nodular regenerative hyperplasia (reticulin stain ×200). Long-term allografts can develop lesions related to altered blood flow through the liver. In this image the reticulin is outlining a nodule, this nodule is not surrounded by fibrous tissue, as seen in cirrhosis, but rather by atrophic liver cell plates. This is one of the lesions in the spectrum of non-cirrhotic portal hypertension. Its natural history in the allograft is at present unclear

11.3.1 Survival

The advances in immunosuppression , organ preservation , refinements of the operative technique and effective antimicrobial prophylaxis have resulted in, pediatric LT being a routine operation with excellent patient outcomes . Survival is 70–90% at 1 year and >80% at 20 years (European Liver transplant registry) (Fig. 11.18). Children regain normal growth and development, enter puberty, complete secondary education, become parents and contribute to society (Fig. 11.19).

Fig. 11.18

Long term survival from the European Liver transplant registry demonstrating more than 90% survival 1 year and 20 years 70–80%

Fig. 11.19

Long term survivors post liver transplant competing in the Transplant Games